Parathyroid hormone (PTH) significantly affects osteoblast function by altering gene expression. We have identified neuron-derived orphan receptor-1 (NOR-1) as a PTH-induced primary gene in osteoblastic cells. NOR-1, Nurr1, and Nur77 comprise the NGFI-B nuclear orphan receptor family and Nurr1 and Nur77 are PTH-induced primary osteoblastic genes. Ten nM PTH maximally induced NOR-1 mRNA at 2 It in primary mouse osteoblasts and at 1 h in mouse calvariae. Cycloheximide pretreatment did not inhibit PTH-induced NOR-1 mRNA. PTH activates cAMP-protein kinase A (PKA), protein kinase C (PKC), and calcium signaling. Forskolin (PKA activator) and PMA (PKC activator) mimicked PTH-induced NOR-1 mRNA. lonomycin (calcium ionophore) and PTH(3-34), which do not activate PKA, failed to induce NOR-1 mRNA. PKA inhibition with H89 blocked PTH- and FSK-induced NOR-1 mRNA. PMA pretreatment to deplete PKC inhibited PMA-induced, but not PTH-induced, NOR-1 mRNA. We conclude that NOR-1 is a PTH-regulated primary osteoblastic gene that is induced mainly through cAMP-PKA signaling. (C) 2003 Elsevier Science (USA). All rights reserved.